title: RYR1 mutations as a cause of ophthalmoplegia, facial weakness, and malignant hyperthermia.
abstract: OBJECTIVE
  Total ophthalmoplegia can result from ryanodine receptor 1 (RYR1) mutations without overt associated skeletal myopathy. Patients carrying RYR1 mutations are at high risk of developing malignant hyperthermia. Ophthalmologists should be familiar with these important clinical associations.
  
  
  OBJECTIVE
  To determine the genetic cause of congenital ptosis, ophthalmoplegia, facial paralysis, and mild hypotonia segregating in 2 pedigrees diagnosed with atypical Moebius syndrome or congenital fibrosis of the extraocular muscles.
  
  
  METHODS
  Clinical data including medical and family histories were collected at research laboratories at Boston Children's Hospital and Jules Stein Eye Institute (Engle and Demer labs) for affected and unaffected family members from 2 pedigrees in which patients presented with total ophthalmoplegia, facial weakness, and myopathy.
  
  
  METHODS
  Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed.
  
  
  METHODS
  Mutations in RYR1.
  
  
  RESULTS
  Missense mutations resulting in 2 homozygous RYR1 amino acid substitutions (E989G and R3772W) and 2 compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in a consanguineous and a nonconsanguineous pedigree, respectively. Orbital magnetic resonance imaging revealed marked hypoplasia of extraocular muscles and intraorbital cranial nerves. Skeletal muscle biopsy specimens revealed nonspecific myopathic changes. Clinically, the patients' ophthalmoplegia and facial weakness were far more significant than their hypotonia and limb weakness and were accompanied by an unrecognized susceptibility to malignant hyperthermia.
  
  
  CONCLUSIONS
  Affected children presenting with severe congenital ophthalmoplegia and facial weakness in the setting of only mild skeletal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were susceptible to malignant hyperthermia. While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical because they lacked significant weakness, respiratory insufficiency, or scoliosis. RYR1-associated myopathies should be included in the differential diagnosis of congenital ophthalmoplegia and facial weakness, even without clinical skeletal myopathy. These patients should also be considered susceptible to malignant hyperthermia, a life-threatening anesthetic complication avoidable if anticipated presurgically.
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts2F. B. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts3Program in Genomics, Boston Children's Hospital, Boston, Massachusetts4Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts5Dubai Harvard Foundation for Medical Research, Boston, Massachusetts.
authors.forename: Sherin
authors.initials: S
authors.lastname: Shaaban
authors.affiliation: Division of Pediatric Neurology, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ramos-Platt
authors.affiliation: Division of Pathology (Neuropathology), Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Floyd H
authors.initials: FH
authors.lastname: Gilles
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts3Program in Genomics, Boston Children's Hospital, Boston, Massachusetts8Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts2F. B. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts8Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts10Department of Pathology, Harvard Medical School, Boston, Massachusetts11Division of Neuropathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Umberto
authors.initials: U
authors.lastname: De Girolami
authors.affiliation: Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles13Department of Neurology, Jules Stein Eye Institute, University of California, Los Angeles14Department of Bioengineering, Jules Stein Eye Institute, University of California, Los Angeles15Neuroscience Interdepartmental Programs, Jules Stein Eye Institute, University of California, Los Angeles.
authors.forename: Joseph
authors.initials: J
authors.lastname: Demer
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts2F. B. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts3Program in Genomics, Boston Children's Hospital, Boston, Massachusetts4Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts8Howard Hughes Medical Institute, Chevy Chase, Maryland16Department of Medicine (Genetics), Boston Children's Hospital, Boston, Massachusetts17Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts18Department of Neurology, Harvard Medical School, Boston, Massachusetts19Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts20Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D019943:Amino Acid Substitution; D001763:Blepharoptosis / Q000175:diagnosis / Q000235:genetics; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004200:Diseases in Twins / Q000235:genetics; D059472:Exome / Q000235:genetics; D015785:Eye Diseases, Hereditary / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005355:Fibrosis; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008305:Malignant Hyperthermia / Q000175:diagnosis / Q000235:genetics*; D020331:Mobius Syndrome / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D009886:Ophthalmoplegia; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D014429:Twins, Dizygotic / Q000235:genetics; D000093922:Congenital Cranial Dysinnervation Disorders
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel